Preparation method of telmisartan intermediate

A technology for telmisartan and intermediates, applied in the field of preparation of telmisartan intermediate 2-n-propyl-4-methyl-6-carboxybenzimidazole, which can solve the problem that the process route is not easy to control, color Not easy to remove, unstable product quality and other problems, to achieve the effect of improving production safety, avoiding carboxyl esterification, and reducing alkali hydrolysis

Active Publication Date: 2019-02-12
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In summary, the existing 2-n-propyl-4-methyl-6-carboxybenzimidazole preparation process has defects such as unstable product quality and difficult control of the process route.
And

Method used

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  • Preparation method of telmisartan intermediate
  • Preparation method of telmisartan intermediate
  • Preparation method of telmisartan intermediate

Examples

Experimental program
Comparison scheme
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Example Embodiment

[0046] Example 1.

[0047] Step 1. Add 150 g of hydrochloric acid ethanol and 250 g of butyronitrile to the reaction flask R1, control the temperature at 20°C and maintain it, slowly pass in 125 g of anhydrous hydrogen chloride gas, and stir and react for 2 hours after the aeration is completed. Put 550 g of xylene into R1 to obtain a butyronitrile salt solution containing intermediates V and IV.

[0048] Step 2. Put 64g of sodium carbonate and 370g of water into the reaction flask R2, stir until it is clear, add 1500g of xylene, control the temperature to 10℃ and maintain, under stirring, start double-dropping the sodium hydroxide solution and the butyl obtained in step 1. Nitrile salt solution, maintain the pH value of 6.1, after the addition is complete, stir for 2h. Separate the lower water phase and transfer the materials to the R3 reaction flask. Under stirring, add 360 g of anhydrous methanol, 200 g of aminobenzoic acid, and 80 g of glacial acetic acid to the reaction flas...

Example Embodiment

[0050] Example 2.

[0051] Step 1. Add 75 g of hydrochloric acid and ethanol, 250 g of butyronitrile to the reaction flask R1, control the temperature at 0°C and maintain it, and slowly pass in 163 g of anhydrous hydrogen chloride gas. After the aeration is completed, stir and react for 1.5 hours. Put 500 g of xylene into R1 to obtain a butyronitrile salt solution containing intermediates V and IV.

[0052] Step 2. Put 62.5g of sodium carbonate and 370g of water into the reaction flask R2, stir until it is clear, add 1700g of xylene, control the temperature to 0℃ and maintain it, under stirring, start double-dropping the sodium hydroxide solution and the result of step 1. Nitrile salt solution, maintain the pH value of 11.0, after the dropwise addition is completed, stir for 1.5h. Separate the lower water phase and transfer the materials to the R3 reaction flask. Under stirring, 300 g of anhydrous methanol, 198 g of aminobenzoic acid, and 86 g of glacial acetic acid were added to...

Example Embodiment

[0054] Example 3.

[0055] Step 1. Add 200 g of hydrochloric acid ethanol and 250 g of butyronitrile to the reaction flask R1. The temperature is controlled and maintained at 35°C. 117.5 g of anhydrous hydrogen chloride gas is slowly introduced. After the aeration is completed, the reaction is stirred for 1.5 hours. Put 500 g of xylene into R1 to obtain a butyronitrile salt solution containing intermediates V and IV.

[0056] Step 2. Put 67.6g of sodium carbonate and 370g of water into the reaction flask R2, stir until it is clear, add 1400g of xylene, control the temperature to 20°C and maintain it, under stirring, start double-dropping the sodium hydroxide solution and the result of step 1. Nitrile salt solution, maintain the pH value of 5.0, after the addition is complete, stir for 1.5h. Separate the lower water phase and transfer the materials to the R3 reaction flask. Under stirring, add 370 g of anhydrous methanol, 232 g of aminobenzoic acid, and 76 g of glacial acetic acid...

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Abstract

The invention relates to a preparation method of a telmisartan intermediate, namely 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid. The preparation method of the 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid comprises the following steps: firstly, ethanol hydrochloride acts with butyronitrile and anhydrous hydrogen chloride within the range of 0-35 DEG C; the mixture obtained in the firststep reacts with 3-methyl-4-aminobenzoic acid and ice vinegar within the range of pH 5.0-11.0 at the controlled temperature of 10-40 DEG C, and an intermediate shown in the formula II is obtained; and then the intermediate shown in the formula II reacts with a sodium hypochlorite solution, and the 2-n-propyl-4-methyl-6-Benzimidazolecarboxylic acid is obtained. The intermediate preparation processis suitable for industrial production, and meanwhile the product quality is improved.

Description

technical field [0001] The invention relates to a preparation method of telmisartan intermediate 2-n-propyl-4-methyl-6-carboxybenzimidazole, which belongs to the technical field of pharmacy. Background technique [0002] Telmisartan is a new type of antihypertensive drug and a specific angiotensin II receptor (AT1 type) antagonist. Telmisartan substitutes for the angiotensin II receptor and binds with high affinity to the AT1 receptor subtype (the known site of action of angiotensin II). Telmisartan has no agonist effect at the AT1 receptor site, and Telmisartan selectively binds to the AT1 receptor, and the binding effect is long-lasting. Telmisartan was first developed by the German Boehringer Ingelheim pharmaceutical company (Boehringer Ingelheim), and was first launched in the United States in March 1999, and then in many countries around the world such as Germany and the United Kingdom. [0003] 2-n-propyl-4-methyl-6-carboxybenzimidazole (formula I, also known as mono...

Claims

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Application Information

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IPC IPC(8): C07D235/08
CPCC07D235/08
Inventor 苗华明李靖金鑫徐永超张龙
Owner 迪嘉药业集团股份有限公司
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